补骨胶囊与17α-炔雌醇联合用药对大鼠骨质疏松的预防及对子宫刺激作用的研究

目的 观察补骨胶囊与17α-炔雌醇联合用药对去卵巢大鼠骨质疏松的预防作用及对子宫的刺激作用。方法 47只4月龄SD雌性大鼠随机分为6组：①假手术组；②去卵巢组；③高剂量及④低剂量17α-炔雌醇预防组；⑤补骨胶囊预防组；⑥补骨胶囊与低剂量17α-炔雌醇联合用药组。实验12周。通过骨组织形态计量学方法分析大鼠骨量变化情况，通过测量子宫湿重及内膜厚度分析用药对子宫的刺激作用。结果 去卵巢组骨小梁面积百分率(Tb．Ar％)比假手术组显著下降，高剂量17α-炔雌醇组和联合用药组Tb．Ar％比去卵巢组显著增加。高、低剂量17α-炔雌醇组与去卵巢组比，子宫湿重及内膜厚度都显著增加；联合用药组与两个17α-炔雌醇组比，子宫湿重及内膜厚度显著降低。结论补骨胶囊与17α-炔雌醇联合用药可有效预防去卵巢大鼠骨质疏松，与单独使用17α-炔雌醇比，对子宫刺激作用显著降低。     

中药骨康对去卵巢大鼠腰椎骨形态计量学的影响

目的 探讨中药骨康对卵巢切除大鼠骨质疏松症的治疗作用。方法 选择6m龄SD大鼠48只。随机分为假手术模型组（Sham）、手术模型组（OVX）、尼尔雌醇组（E2）、中药骨康组。切除大鼠卵巢3m后。大鼠骨质疏松症模型制备成功，分别给予尼尔雌醇、中药骨康灌胃治疗，并与Sham组和OVX组对照。治疗3m后，体内双荧光标记，取第2腰椎包埋切片。全自动图像分析及松质骨骨形态计量学软件处理。观察中药对骨形态计量学参数的影响。结果 卵巢切除后大鼠骨小梁面积百分数（％Tb．Ar）下降35．84％，骨小梁数量（Tb．N）下降16．60％，骨小梁宽度（Tb．Th）下降25．79％，表明绝经后骨质疏松症动物模型成立。骨康治疗3个月后，与OVX组相比，Oc．N／mm^2下降42．80％，有显著性差异（P〈0．01）；％Tb．Ar、Tb．Th、Tb．N和MAR有上升趋势（P〉0．05）；15．Sp，％L．Pm、BFR／BS、BFR／TV和Oc．N／mm，BFR／BV有下降趋势（P〉0．05）。结论 中药骨康具有降低骨转换以及促进骨形成和抑制骨吸收的双重作用，说明中药骨康对骨质疏松有明显的治疗作用。     

依普拉芬与17α-炔雌醇合用对去卵巢大鼠子宫和骨的影响

目的观察依普拉芬能否抑制17α-炔雌醇刺激子宫副作用,及对炔雌醇抗骨质疏松作用的影响。方法52只4月龄SD雌性大鼠随机分为6组:①假手术组;②去卵巢组;③高炔雌醇组(30μg·kg-1·d-1);④低炔雌醇组(6μg·kg-1·d-1);⑤依普拉芬(200mg·kg-1·d-1);⑥联合用药组(炔雌醇6μg·kg-1·d-1+依普拉芬200mg·kg-1·d-1)。实验12周,通过测量子宫内膜厚度及子宫湿重分析用药对子宫的刺激作用,测量骨小梁面积百分率(%Tb.Ar)、荧光周长百分数(%L.Pm)及破骨细胞数量(Oc.N分别反映骨量、骨形成及骨吸收的变化)。结果高、低炔雌醇组与去卵巢组比,%Tb.Ar增加,%L.Pm、Oc.N减少,子宫湿重及内膜厚度都显著增加。依普拉芬组与去卵巢组比,子宫湿重及内膜厚度、%Tb.Ar、%L.Pm无显著性差异,Oc.N减少。联合用药组与去卵巢组比,%Tb.Ar增加;与低炔雌醇组比,子宫重量、内膜厚度显著降低,联合用药组与正常对照组的子宫内膜厚度无显著性差异。结论依普拉芬可有效抑制炔雌醇对大鼠子宫刺激作用,与炔雌醇合用可有效防治骨质疏松。     

淫羊藿总黄酮和戊酸雌二醇对骨质疏松症大鼠TGF-β1/Smads信号通路的影响

目的 研究淫羊藿总黄酮和戊酸雌二醇对骨质疏松症大鼠TGF-β1/Smads信号通路的影响。方法 75只雌性SD大鼠随机分为假手术组（Sham组）、模型组（Model组）、淫羊藿总黄酮组（TFE组）、戊酸雌二醇组（E2V组）、淫羊藿总黄酮联合戊酸雌二醇组（TFE+E2V组）,行双侧卵巢切除术造模,术后12周开始给予相应的药物干预12周。分别检测血清骨代谢指标,BMD和骨灰重比,骨骼生物力学参数,股骨形态计量学参数,股骨TGF-β1/Smads蛋白和mRNA表达。结果 模型组血清Ca、P、OC、PINP,股骨和椎体骨密度、灰重比,股骨最大载荷、最大位移、最大应力、弹性模量,股骨Tb.Ar、Tb.Th、Tb.N,股骨TGF-β1、Smads2蛋白和mRNA表达较Sham组均显著降低（P＜0.01）,E2V组、TFE组、TFE＋E2V组上述指标较模型组均显著增加（P＜0.05）,TFE＋E2V组上述指标较E2V组、TFE组均显著增加（P＜0.05）。模型组血清ALP,股骨Tb.Sp、Oc.N较Sham组显著增加（P＜0.01）,E2V组、TFE组、TFE＋E2V组上述指标较模型组均显著降低（P＜0.05）,TFE＋E2V组上述指标较E2V组、TFE组均显著降低（P＜0.05）。结论 淫羊藿总黄酮联合戊酸雌二醇通过上调TGF-β1、Smad2表达,调节骨质疏松大鼠骨代谢,增加骨量,提高骨密度和骨强度,从而起到抗骨质疏松作用。     

淫羊藿总黄酮对去卵巢大鼠骨组织OPG、 OPGL mRNA表达的影响

目的：探讨淫羊藿总黄酮（totalflavoneofepimedium,TFE）治疗骨质疏松症的分子机制,为传统中药的现代化和二次开发提供实验依据。方法：将60只4月龄健康雌性SD大鼠按随机数字表法分为对照组（A组,20只,行假手术处理）,去卵巢纽（OVX组,20只,切除卵巢后不给予淫羊藿处理）,淫羊藿组（TFE纽,20只,切除卵巢后给予淫羊藿灌胃）。所有大鼠术前及术后4周以DEXA骨密度仪检测L4骨密度变化（若BMD下降〉20％,则骨质疏松模型建立）。模型建立后TFE组大鼠给予淫羊藿总黄酮（浓度30mg／ml,10ml／kg,1次／d）灌胃4周。所有大鼠处死前再行DEXA骨密度检测,过量麻醉法处死后取其股骨下部,切片匀浆提取骨组织中RNA,应用逆转录一聚合酶链反应（RT—PCR）技术检测骨组织护骨素（osteoprotegrin,OPG）、护骨素配体（0PGL）mRNA的表达。结果：①TFE组大鼠切除卵巢4周后,腰椎BMD均值降至（0．084±0．020）g／cm^2,降幅〉20％证明骨质疏松模型建立。TFE灌胃4周后其腰椎BMD提高至（0．112±0．009）g／cm^2,与给药前比较有明显改善,差异有统计学意义（P〈0．05）;②TFE组大鼠骨组织中OPGmR—NA的表达较OVX组相比,明显增强,且有统计学差异（P〈0．05）,但对OPGLmRNA表达促进作用不明显,组间无统计学差异（P〉0．05）。结论：TFE是通过促进骨组织中OPGmRNA的表达来抑制破骨细胞的分化和成熟,从而达到治疗骨质疏松症的目的。     

芪藿肾宝与己烯雌酚对去卵巢大鼠骨代谢的影响

用３月龄去卵巢ＳＤ大鼠为模型，４．５ｍｇ．Ｌ－１己烯雌酚（ＤＥＳ）按５ｍｌ·ｋｇ－１ｉｇ，３３０ｇ·Ｌ－１的芪藿肾宝（含淫羊蕾，黄芪，白术）按５ｍｌ·ｋｇ－１ｉｇ，每周６次，持续１２周，胫骨近端不脱钙骨片测量。结果：己烯雌酚仅部分抑制去卵巢后的骨高转换，未能完全预防小梁骨的丢失（（％Ｔｂ．Ａｒ－２８％）；芪藿肾宝能完全预防去卵巢大鼠的骨质疏松，其作用机理同样是抑制去卵巢后的骨高转换，但以抑制骨吸收为主，从而防止了骨质疏松的发生。     

BEMF对卵巢切除骨质疏松大鼠治疗作用的骨形态计量学研究

目的观察BEMF对OVX—OP大鼠骨形态计量学指标的影响，探讨BEMF对卵巢切除致骨质疏松大鼠的治疗作用及机制。方法6个月龄雌性未孕Wistar大鼠40只，按体质量随机分为卵巢切除组（OVX）、假手术组（Sham）、仿生电磁场治疗组（EM）、雌激素治疗组（E）。术后8周，E组苯甲酸雌二醇肌肉注射，0．5mg／kg，1次，2周。EM组大鼠暴露于仿生电磁场治疗，1h·次^-1·d^-1，OVX、Sham组不予以任何处理，作为对照组。治疗10周后处死各组大鼠，取左侧胫骨进行骨形态计量学测定。结果治疗10周后，EM组大鼠％Tb．Ar、Tb．Th、Tb．N较OVX组显著增加（P〈0．01），Tb．sp显著降低（P〈0．01），与E组变化相似。E组、EM组大鼠成骨细胞数（％L．Pm）低于OVX组（P〈0．01）；EM组、E组仍高于Sham组（P〈0．01）；EM组高于E组（P〈0．01）。E组、EM组破骨细胞数（N．Oc）低于OVX组（P〈0．01）；EM组、E组仍高于Sham组，（P〈0．01）；EM组高于E组，差异非常显著（P〈0．01）。结论BEMF具有增加骨量、改善骨结构的作用；与雌激素的治疗作用存在不同机制。     

淫羊藿总黄酮对摘除卵巢大鼠骨质疏松症的防治作用

用除卵巢法结合低钙饲料建立大鼠骨质疏松模型。淫羊藿总黄酮在75-300mg/kg剂量范围内连续给药3个月，与模型组大鼠比较，能明显提高大鼠股骨表现观面密度（W/LD）和骨密度（BMD）而不升高子宫系数及血清雌二醇（s-E2)水平，并有提高骨Ca、骨P的趋势。高剂量组大鼠血清碱性磷酸酶（s-ALP)降低，股骨骨密度升高。骨形态计量学结果表明，高剂量组大鼠骨小梁吸收表面百分率（TRS%）和形成表面百分率（TFS%）等参数明显降低，骨小梁体积百分率（TBV%）明显提高。     

去卵巢对大鼠骨密度的影响

目的：探讨去卵巢对大鼠骨密度（BMD）的影响。方法；20只3．5月龄SD雌性大鼠分别除双侧卵巢（OVX）或假性去卵巢（Sham)，术后14周处死，应用QDR－4500A型扇形束双能X射线吸收法（DXA）测量大鼠全身、离体股骨、胫骨、腰维及兴趣区的BMD。结果：①术后6周OVX组全身BMD显低Sham组（P＝0．048），术后14周两组无显性差异；②术后14周OVX组离体股骨BMD显低于Sham组（P＜0．01），股骨远侧干骺端平均降低11．6％（P＜0．001）；③术后14周右侧离体胫骨BMD两组间差异无显性，但OVX组胫骨的端干骺端BMD显低于Sham组（P＜0．001）；④术后14周OVX组腰椎（L4－L6）的BMD显低于Sham组（P＝0．014），第六腰椎降低明显，平均降低8．1％（P＝0．005）。结论：去卵巢所致骨丢失以松质骨含量丰富的兴趣区明显。     

白藜芦醇抗切除卵巢大鼠发生骨质疏松的作用研究

目的研究白藜芦醇(resveratrol,R)抗切除卵巢大鼠发生骨质疏松的作用。方法 6月龄Wistar雌性大鼠40只,随机数字表法分为假手术组(Sham)、去卵巢组(OVX)、淫羊藿苷组(I)和白藜芦醇组(R)。I组给予25 mg/(kg·d)的淫羊藿苷灌胃,R组给予8.4 mg/(kg·d)的白藜芦醇灌胃,Sham和OVX组灌胃等体积蒸馏水。根据体质量每两周进行一次灌胃剂量调整。8周后待各组间骨密度出现显著性差异后立即处死,统计大鼠体质量并计算大鼠器官指数,检测离体骨密度、骨生物力学、血清生化指标,观察骨组织形态并测量分析骨小梁相关静态参数。结果各组大鼠体质量并未出现统计学差异,除子宫系数外其他器官指数无统计学差异(P0.05),但OVX组的子宫指数显著低于Sham组(P0.05),I组和R组子宫指数显著高于OVX组(P0.05);与OVX组相比,I组和R组的骨密度、最大载荷、弹性模量、骨形成指标OC以及Tb.N、BV/TV均显著升高(P0.05),而骨吸收指标TRACP-5b含量和Tb.SP均显著降低(P0.01);骨组织形态观察结果也显示I组和R组骨小梁网状结构呈致密性增加,骨小梁数目明显变多。R组与I组相比,其各指标平均值略低于I组,差异均无统计学意义(P0.05)。结论白藜芦醇可能通过增加骨密度、提高骨强度、促进骨形成、抑制骨吸收、改善骨质量从而发挥抗骨质疏松的作用。     

Simvastatin induces estrogen receptor-alpha expression in bone,restores bone loss,and decreases ERα expression and uterine wet weight in ovariectomized rats

We previously reported that simvastatin induces estrogen receptor-alpha (ERα) in murine bone marrow stromal cells in vitro. In this study, we investigated the effect of simvastatin on ERα expression in bone and uterus in ovariectomized (OVX) rats and evaluated bone mass, bone strength, and uterine wet weight. Three-month-old Sprague–Dawley female rats received OVX or sham operation. Six weeks later, the rats were treated orally with simvastatin (5 or 10 mg/kg/day), or intraperitoneally with 17-β-estradiol (E₂) or a combination of simvastatin and E₂ for 6 weeks. Uterine wet weight, bone mineral density (BMD) of lumbar vertebrae, biomechanics of lumbar vertebrae, and induction of ERα expression in the bone and uterus were analyzed. The 6-week simvastatin treatment improved lumbar vertebral BMD and boosted biomechanical performance of the vertebral body compared to the OVX control, suggesting that simvastatin can treat osteoporosis caused by estrogen deficiency. More interestingly, simvastatin could increase ERα expression and synergy with estradiol in bone while antagonizing estradiol in the uterus, along with uterus atrophy and uterine wet weight decreases. In conclusion, these data suggest that simvastatin exert opposing modulatory effects on ERα expression on bone and uterus in ovariectomized rats, inducing ERα expression and synergy with estrogen to perform anabolic effects on the bones while decreasing E2 efficacy and uterine wet weight. This finding may be helpful to explain the mechanism of statin treatment in osteoporosis caused by estrogen deficiency.     

The effects of nandrolone decanoate on bone mass and metabolism in ovariectomized rats with osteopenia

The effects of nandrolone decanoate (ND) treatment on bone mass and metabolism were studied in ovariectomized (OVX) rats with osteopenia. The 6-month-old rats were divided into Sham (n = 12) and OVX (n = 24). The OVX rats were allowed to lose bone for 6 weeks. At 6 weeks post ovariectomy, the OVX rats were divided into two groups: (1) OVX + Vehicle and (2) OVX + ND. The effects of ND on bone mineral density (BMD), bone mineral content (BMC), and bone metabolism were studied by dual-energy X-ray absorptiometry (DXA) and biochemical markers including urinary pyridinoline (Pyr), deoxypyridinoline (Dpyr), and serum osteocalcin. After 24 weeks of treatment, histomorphometry of the right tibiae and the wet weight of the gastrocnemius and soleus skeletal muscles were also examined. Ovariectomy resulted in a significant increase in biochemical markers and a significant decrease in spine BMD (0.221 ± 0.016 g/cm² in OVX group vs 0.239 ± 0.008 g/cm² in Sham group) and BMC (0.550 ± 0.055 g in OVX group vs 0.605 ± 0.042 g in Sham group) at 6 weeks post ovariectomy. Spine BMD (0.227 ± 0.017 g/cm²), femoral BMD (0.263 ± 0.012 g/cm²), and bone density of femur (1.035 ± 0.036 g/cm³) in the OVX + ND group were significantly greater than those in the OVX + Vehicle group (0.204 ± 0.013 g/cm² for spine BMD, 0.243 ± 0.009 g/cm² for femoral BMD, 0.938 ± 0.06 g/cm³ for bone density of femur) after 24 weeks of treatment. ND treatment decreased urinary Pyr and Dpyr significantly in OVX rats. Histomorphometric findings indicated that ND-treated rats had greater cancellous bone volume, greater trabecular number, greater trabecular thickness, and less trabecular separation than vehicle-treated OVX rats. OVX rats had greater wet weight of the gastrocnemius and soleus muscles than rats treated with ND. The data suggest that the effect of ND on bone mass is not influenced by the condition of the muscles in OVX rats. Our findings indicate that ND blocks further bone loss by inhibition of bone resorption in OVX rats with osteopenia. Received: August 25, 1999 / Accepted: January 28, 2000     

Long-term sensitivity of uterus and hypothalamus/pituitary axis to 17beta-estradiol is higher than that of bone in rats.

We examined the long-term sensitivity of uterus and bone to low-dose 17beta-estradiol in a 4-month experiment in OVX rats and found that a dose of estradiol that fully protected against uterine atrophy did not protect against bone loss. Our results suggest higher estrogen sensitivity of the uterus compared with bone. INTRODUCTION: Estrogen is essential for the function of reproductive tissues and for the normal acquisition and maintenance of bone mass in females. This study was designed to examine the long-term sensitivity of the uterus and bone to low-dose estrogen. MATERIALS AND METHODS: In preliminary experiments, we determined the lowest subcutaneous dose of 17beta-estradiol able to fully protect against uterine atrophy in ovariectomized (OVX) rats. This dose was found to be 1.5 microg/kg, given five times per week. Subsequently, groups of sham-operated (SHAM) or OVX 6-month-old rats (n = 8 each) were subcutaneously injected with vehicle or 1.5 microg/kg 17beta-estradiol five times per week. All animals were killed 4 months after surgery. Serum osteocalcin and urinary deoxypyridinoline were measured as biochemical markers of bone turnover. Bones were analyzed by bone histomorphometry and pQCT. RESULTS AND CONCLUSIONS: Our study clearly showed that a dose of estradiol that restores physiological estradiol serum levels, fully maintains uterine weight in OVX rats at the SHAM control level, and suppresses serum follicle-stimulating hormone (FSH) by 67% relative to OVX vehicle controls does not provide significant protection against OVX-induced bone loss at different cancellous and cortical bone sites. We conclude that the long-term sensitivity of the uterus and the hypothalamus/pituitary axis to 17beta-estradiol is higher than that of bone in rats.     

孕激素对去势雌性大鼠骨密度及骨形态计量作用的初步研究

目的　了解孕激素对去势雌性大鼠骨密度及骨形态计量作用。方法　 5 0只 6月龄Wistar雌性大鼠随机分为 5组 :假手术组和卵巢切除组、卵巢切除后分别加安宫黄体酮 2mg组、安宫黄体酮 2 0mg组和倍美力组。手术后 7d喂药 ,用药后 3个月处死。测定各组大鼠子宫湿重、全身及股骨骨密度并取大鼠椎骨、胫骨组织切片进行形态计量分析。结果　两组孕激素组子宫湿重与卵巢切除组相同 ,均显著低于假手术组与倍美力组 (P <0 0 0 1)。假手术、雌、孕激素组全身骨密度测定均大于卵巢切除组 (P <0 0 5 )。各组股骨骨密度无显著差异。组织切片观察显示 ,假手术与倍美力组骨小梁粗壮、饱满、结构完整 ;卵巢切除组则纤细、断裂、完整性差。孕激素组骨小梁结构优于卵巢切除组但不及假手术及倍美力组。计量分析显示孕激素组椎骨骨小梁面积明显大于卵巢切除组(P <0 0 5 ) ,但低于倍美力组 (P <0 0 5 )。胫骨骨小梁面积与卵巢切除组相仿 ,均明显低于假手术和倍美力组 (P <0 0 5 )。孕激素 2mg与 2 0mg组间无明显差异。结论　两种剂量的安宫黄体酮对卵巢切除大鼠骨质疏松均有一定防治作用 ,但从骨组织形态计量分析 ,其作用较弱 ,与结合雌激素相比 ,尚不足以维持骨量     

苯甲酸雌二醇对绝经后骨质疏松模型大鼠子宫内膜及子宫肥大细胞数量的影响

目的运用组织学和组织化学的方法观察苯甲酸雌二醇对绝经后骨质疏松模型大鼠子宫形态和子宫肥大细胞数量的影响。方法 3月龄健康雌性SD大鼠随机分为手术组(OVX组)和假手术组(Sham组),手术组实施双侧卵巢去除手术,手术后3个月将大鼠分为OVX组、OVX+E2组、Sham组,每组6只,OVX+E2组腹腔注射苯甲酸雌二醇20μg/(kg·d),每隔1天给药1次,连续给药28 d,OVX组和Sham组腹腔注射花生油作对照。给药结束后采集大鼠子宫常规石蜡包埋、切片,分别进行HE染色和改良甲苯胺蓝染色观察子宫形态并计数子宫横断面肥大细胞的数量。结果绝经后骨质疏松模型大鼠子宫明显萎缩,子宫腔径、子宫黏膜上皮厚度均较正常大鼠减小(P0.01),给药苯甲酸雌二醇28 d后观察发现子宫腔径、子宫黏膜上皮厚度均恢复正常。对子宫肥大细胞的观察发现大鼠子宫肥大细胞均集中分布于子宫黏膜肌层、平滑肌束间结缔组织近小血管壁处,以微血管附近居多,子宫内膜内偶见。去卵巢后大鼠子宫肥大细胞较正常组显著增多(P0.01),给药苯甲酸雌二醇后子宫肥大细胞数量趋于正常。结论提示卵巢雌激素在局部免疫调节中发挥重要作用。     

Effects of SP500263, a Novel Selective Estrogen Receptor Modulator, on Bone, Uterus, and Serum Cholesterol in the Ovariectomized Rat

We describe here the activity of a novel selective estrogen receptor modulator, SP500263. When given to adult ovariectomized (OVX) rats for 28 days at doses of 0.3, 1, or 3 mg/kg/day, we found that SP500263 partially protected against OVX-induced loss of bone mineral content in the distal ends of femurs and in the whole bone. SP500263 also antagonized the OVX-induced increase in body weight. However, unlike 17-estradiol, SP500263 at efficacious doses did not prevent the OVX-induced loss in uterine wet weight. A small but significant effect on uterine wet weight was noted with raloxifene dosed at 1 mg/kg. As expected, SP500263 but not raloxifene acted as an estrogen antagonist on the uterus in adult rats when administered for 7 days at 30 mg/kg/day. Finally, SP500263 had no statistically significant effects on total serum cholesterol and serum triglycerides in OVX rats treated for 28 days. Raloxifene had no significant effects on body weight, bone mineral content, and serum cholesterol or triglycerides in the OVX-rat model. In summary, SP500263 is a new orally active SERM that acts in rats as an estrogen agonist on bone without causing uterine stimulatory effects. Present addresses: M. Kung Sutherland, Celltech R&D, Inc., Bothell, WA 98021, USA. L. M. Gayo-Fung, Structural Genomix Inc., San Diego, CA 92121, USA. E. OLeary, Chugai Pharma,USA, San Diego, CA 92121, USA, D. W. Anderson, Graceland University, Lamoni, IA 50140, USA.     

Skeletal effects of bazedoxifene paired with conjugated estrogens in ovariectomized rats

A novel approach to menopausal therapy is the tissue selective estrogen complex (TSEC) that partners bazedoxifene (BZA) with conjugated estrogens (CE). We examined the effects of daily treatment with BZA 0.3mg/kg, CE 2.5mg/kg, or combined BZA/CE (BZA 0.1, 0.3, or 1.0mg/kg with CE 2.5mg/kg) over 12months on bone mass, bone architecture and strength, and biochemical markers of bone turnover in ovariectomized (OVX) female Sprague-Dawley rats vs OVX control rats. Total cholesterol and uterine weights were also evaluated. All BZA/CE dose combinations prevented ovariectomy-induced increases in bone turnover and significantly increased bone mineral density (BMD) at the lumbar spine, proximal femur, and tibia compared with OVX controls. All BZA/CE doses evaluated also prevented many of the ovariectomy-induced changes of the static and dynamic parameters of the cortical compartment of the tibia and the cancellous compartment of the L1 and L2 vertebrae. All BZA/CE doses increased biomechanical strength at the lumbar spine (L4) compared with OVX animals. The co-administration of BZA 0.3 and 1.0mg/kg/day with CE 2.5mg/kg/day showed a dose-dependent reduction in uterine wet weight compared with administration of CE alone. All BZA/CE doses significantly lowered total cholesterol levels compared with OVX controls. In conclusion, 12months of treatment with BZA/CE in OVX rats effectively maintained BMD, bone microstructure, and bone quality; and the pairing of BZA with CE prevented CE-induced uterine stimulation.     

神经肽在去卵巢大鼠骨组织中表达差异的实验研究

目的探讨神经肽P物质(substance P,SP),降钙素基因相关肽(calcitonin gene-related peptide,CGRP),血管活性肠肽(vasoactive intestinal peptide,VIP)和神经肽Y(neuropeptide Y,NPY)在去卵巢组(ovariectomized,OVX)大鼠和假手术组(sham-operated,Sham)大鼠胫骨干骺端表达的差异以及与骨密度(bone mineral density,BMD)的相关性。方法 12只6月龄雌性未孕SD大鼠随机分为Sham组和OVX组,每组6只。造模后12 w两组大鼠称量体重后处死,取大鼠子宫称重,双能X线检测大鼠胫骨干骺端BMD,免疫组织化学法观察两组大鼠右侧胫骨干骺端SP,CGRP,VIP和NPY表达,取平均光密度(mean optical density,MOD)值,分析其与BMD之间相关性。结果造模后12 w,与Sham组相比较,OVX组大鼠体重增加,子宫湿重和BMD值降低,免疫组织化学法观察发现SP,CGRP和VIP的MOD值降低,NPY的MOD值升高,差异具有统计学意义(P0.01)。大鼠SP,VIP的MOD值与BMD值成正相关关系(r=0.746,P=0.005;r=0.591,P=0.043),NPY的MOD值与BMD值成负相关关系(r=-0.666,P=0.018)。结论骨质疏松可能与骨组织中神经肽的表达量改变有关,但其中具体机制有待进一步研究。     

A new selective estrogen receptor modulator, CHF 4227.01, preserves bone mass and microarchitecture in ovariectomized rats.

A new SERM, CHF 4227.01, given to 6-month-old female rats immediately after ovariectomy, preserved bone mass and bone microarchitecture without affecting uterus weight. It also decreased serum cholesterol and fat mass in estrogen-deficient rats. INTRODUCTION: We tested the effect of a new benzopyran derivative, CHF 4227.01, with selective estrogen receptor modulator (SERM) activity on bone mass and biomechanics in ovariectomized (OVX) female rats in comparison with 17alpha-ethinylestradiol (EST), raloxifene (RLX), and lasofoxifene (LFX). MATERIALS AND METHODS: Four doses of CHF 4227.01 (0.001, 0.01, 0.1, and 1 mg/kg body weight [bw]/day) were administered in OVX animals daily by gavage 5 days/week for 4 months. EST was administered at a dose of 0.1 mg/kg bw/day, whereas RLX and LSX were administered at doses of 1 and 0.1 mg/kg bw/day, respectively, by gavage. In one group (Sham), rats were operated but the ovaries not removed; another OVX group was treated only with placebo. RESULTS AND CONCLUSIONS: Treatment with CHF 4227.01 (1.0 and 0.1 mg/kg bw), EST (0.1 mg/kg bw), LFX (0.1 mg/kg bw), or RLX (1.0 mg/kg bw) prevented bone loss on the lumbar spine and the proximal femur assessed in vivo by DXA. Volumetric BMD obtained by pQCT ex vivo confirmed protection from bone loss in the spine and proximal femur among rats treated with CHF 4227.01. This effect was associated with strong inhibition of bone resorption both histologically and biochemically. Furthermore, CHF 4227.01 preserved trabecular microarchitecture, analyzed by muCT, and maintained biomechanical indices of bone strength in the spine and proximal femur, effects also observed for RLX, whereas LSX was less protective of microarchitecture. CHF 4227.01 treatment did not affect uterine weight, prevented the increase in body weight and fat mass seen in OVX animals, and decreased serum cholesterol to below the average of intact animals. In conclusion, CHF 4227.01 exhibits a promising therapeutic and safety profile as a new SERM on both skeletal and extraskeletal outcomes.     

Effects of combined elcatonin and alendronate treatment on the architecture and strength of bone in ovariectomized rats

We examined the combined effects of elcatonin (ECT) and alendronate (ALN) on bone mass, architecture, and strength in ovariectomized (OVX) rats. Fifty female Sprague Dawley rats, aged 13 weeks, were divided into Sham, OVX, OVX+ECT, OVX+ALN, and OVX+ECT+ALN groups (n = 10). Immediately after ovariectomy, ECT was administered at a dose of 15 units (U)/kg three times a week, and ALN was administered daily at a dose of 2.0 µg/kg, subcutaneously for 12 weeks. The three-dimensional architecture of the bone in the distal femoral metaphysis was analyzed using a microfocus X-ray computed tomography system (µCT), and bone strength was measured using a material-testing machine. Trabe-cular bone volume (BV/TV) and number (Tb.N) were significantly greater in the OVX+ECT and OVX+ALN groups than in the OVX group. In the OVX+ECT+ALN group, BV/TV and Tb.N were significantly greater when compared with those in the OVX+ECT and OVX+ALN groups. Trabecular thickness (Tb.Th) was significantly greater in the OVX+ECT+ALN group than in the OVX+ALN group. With regard to bone strength, the compression strength in the femoral metaphysis was significantly lower in the OVX group than in the Sham group. The reduction of compression strength was slightly lower in the OVX+ECT and OVX+ALN groups. In the OVX+ECT+ALN group, the compression strength in the femoral metaphysis significantly increased when compared with the OVX and OVX+ECT groups. These results suggest that the combined treatment of ECT and ALN does not alter the individual effects of each drug and that it exerts an additive effect on trabecular architecture and bone strength in OVX rats.